The purpose of this project is to gain a deeper understanding of allosteric modulation of the metabotropic glutamate receptor subtype 5 (mGluRS), and the role of the receptor in psychiatric disorders, such as schizophrenia. It is hoped that this research will add to a growing body of literature that will lead to more effective psychiatric medication, and thus improved functional outcomes for patients. This project will address two related objectives. First, a novel class of positive allosteric modulators (PAMs) of mGluR5 will be assessed to test the hypothesis that these compounds are binding to a novel site on the receptor. Second, the efficacy of these mGluRS PAMs will be evaluated in animal models to test the hypothesis that the compounds will have antipsychotic and cognitive-enhancing activity. The glutamate hypothesis of schizophrenia states that one cause of the positive and negative symptoms as well as cognitive deficits characteristic of the disease may be a change in signaling through the /V-methyl-D-aspartatereceptor (NMDAR). Direct enhancement of NMDAR function has been found to ameliorate schizophrenic symptoms but has toxic effects. Studies have shown that mGluRS and the NMDAR are closely coupled signaling partners, and activation of mGluRS can potentiate NMDAR current in the hippocampus. Thus activating mGluRS using PAMs can indirectly enhance NMDAR function and consequently ameliorate symptoms of schizophrenia. For the first aim of this project, the domains of mGluRS that are necessary for the function of the novel PAMs will be explored using site-directed mutagenesis. Mutant receptors that inhibit the function of certain mGluRS modulators will be used to determine the effects of the mutants on the actions of the novel compounds. Pharmacological methods based on classical receptor theory will also be used to determine whether the PAMs can compete with ligands that interact with the previously characterized MPEP site. Specifically, Schild analysis will determine whether the neutral allosteric ligand 5MPEP will competitively block the actions of the novel PAMs. For the second aim, behavioral assays will be conducted to establish the effects of these novel compounds. To evaluate antipsychotic efficacy, the ability of compounds to reverse amphetamine-induced hyperlocomotion and amphetamine-induced disruption of prepulse inhibition of the acoustic startle response (PPI) will be investigated. Next, the ability of the PAMs to reverse MK801-induced deficits in attentional set-shifting as a measure of cognitive flexibility will be studied. Public Health Relevance: Current treatment for schizophrenia is not sufficient to treat all symptoms of the disorder, especially the negative symptoms, (i.e. withdrawal) and cognitive deficits. This research is taking a novel pharmacological approach to address this problem, and will focus on the mGluRS receptor in the brain that seems to be involved in regulation of disrupted neurotransmission that leads to schizophrenic symptoms.